Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
PURPOSE: Vortioxetine an anti-depressant FDA-drug recently reported showing better in vitro efficacy against SARS-CoV-2. METHODS: In this study, we have synthesized ten new derivatives having alkenes, alkynes, benzyl, aryl, and mixed carbamate at the N-terminal of vortioxetine. Then the binding energy and interactions with the crucial amino acid residues in the binding pocket of main protease (Mpro) of SARS-CoV-2, of reported and ten newly synthesized vortioxetine derivatives (total thirty-one) in comparison with remdesivir are analyzed and presented in this paper. RESULTS: Based on the docking scores predicted by ADV and AD, most vortioxetine derivatives showed better binding efficiency towards Mpro of SARS-CoV-2 in comparison with remdesivir (an EUA approved drug against SARS-CoV-2 Mpro) and vortioxetine. CONCLUSION: This study shows that some vortioxetine derivatives can be developed into promising drugs for COVID-19 treatment.
COVID-19 Drug Treatment , SARS-CoV-2 , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Vortioxetine/pharmacology
BACKGROUND: There are various studies on younger adults which have shown that neuromuscular electrical stimulation (NMES), at sufficient intensities, combined with active exercises had better improvement in muscle strength and functional performance than exercises alone. But very limited research is available for giving NMES in the early acute stages post total knee arthroplasty (TKA). So, the short-term effect of NMES had not yet been researched upon widely. As there were conflicting evidences in giving NMES post TKA, this study was proposed to assess the short-term effect of early NMES on knee joint pain, range of motion (ROM) and extension lag on patients undergoing bilateral TKA. METHODS: The study included 28 bilateral TKA patients following osteoarthritis (OA) knee within the age group of 50-75 years (60.82±5.69). The knees of 28 bilaterally operated patients were randomly divided into two groups; 1 knee was allocated in the experimental group and the other knee of the same patient became the control. The experimental group was given NMES with exercises, while the control group was given only exercises for 7 days. The patients were asked to continue to follow exercises even after the discharge, i.e., beyond 7 days. The patients were measured for pain; knee flexion ROM and extensor lag both before and after intervention. RESULTS: There was a significant improvement in pain, knee ROM and extensor lag post intervention P<0.05 in both the groups. But there was no significant difference between the groups with respect to pain, knee ROM and extensor lag, P>0.05. CONCLUSIONS: The NMES and exercises worked equally in case of patients operated for TKA. Hence our results concluded that there was no additional effect of NMES on extensor lag, knee ROM and pain when applied for 7 days in patients operated with TKA.
BACKGROUND: Vitamin D, an important hormone required by the body, exerts its biological effects through Vitamin D receptors (VDRs) present on target cells. Vitamin D is ineffective in tissues which lack VDR. Various tissues show the presence of VDRs. However, evidence for the presence of VDRs in human periodontal ligament tissue in fully erupted teeth in adults is lacking. The present study intends to evaluate the presence of VDRs in periodontal ligament (PDL) tissue and assess their response to serum Vitamin D3 levels in chronic periodontic patients. MATERIALS AND METHODS: A total of 19 chronic periodontitis patients were enrolled in the study and tested for serum 25(OH)D3 levels. Deficient patients were supplemented with Vitamin D3. PDL tissue of these patients was isolated after tooth extraction before and after supplementation of Vitamin D3 and analyzed for the presence of VDR in PDL tissue by using enzyme-linked immunosorbent assay. RESULTS: All the chronic periodontitis patients were found to be deficient in Vitamin D3. The mean serum 25(OH)D3 level before supplementation was 13.96 ng/mL which significantly increased to 35.12 ng/mL after supplementation of Vitamin D3 for 6 weeks. VDR analysis determined mean VDR conc. in PDL tissue to be -1.443 ng/mL, which increased to 2.38 ng/mL after supplementation. A concentration dependent correlation was seen between serum 25(OH)D3 levels and VDR conc. in PDL tissue after supplementation. CONCLUSIONS: The study determined Vitamin D Receptors (VDR) in PDL tissue after supplementation of Vitamin D. Thus in addition to the standard treatment modalities, Vitamin D3 supplementation would be an important factor for generation of adequate immune response.
BACKGROUND: Calcium sodium phosphosilicate is a recently introduced desensitizing agent which acts by occluding the dentinal tubules and also resists acid decalcification. This study was designed to assess the efficacy of a new toothpaste containing 5% calcium sodium phosphosilicate for the treatment of dentinal hypersensitivity and also compare it with 5% potassium nitrate. MATERIALS AND METHODS: Sixty patients with the chief complaint of dentinal hypersensitivity were enrolled and randomly divided into two groups. The visual analog scale (VAS) scores were taken for water and air stimuli at baseline, 3 weeks after usage of the respective toothpaste, and 3 weeks after discontinuation of the respective toothpaste. RESULTS: Both the groups showed reduction in hypersensitivity scores at 3 weeks and 6 weeks for air stimulus and cold water. The calcium sodium phosphosilicate group, however, showed significantly reduction in hypersensitivity compared to the potassium nitrate group at any time point for both measures of hypersensitivity. CONCLUSION: The 5% calcium sodium phosphosilicate group showed immense reduction in dentinal hypersensitivity symptoms. The 5% calcium sodium phosphosilicate showed prolonged effects even after discontinuation as compared to 5% potassium nitrate, due to its dentinal tubular occlusion property.
Periodontitis is an infectious disease with marked inflammatory response, leading to destruction of underlying tissues. The aim of periodontal therapy is to eradicate the pathogens associated with the disease and attain periodontal health. This is achieved by non-surgical and surgical therapy; however, mechanical debridement and topical application of antiseptics may not be helpful in all cases. In such cases, adjunctive systemic antibiotic therapy remains the treatment of choice. It can reach micro-organisms at the base of the deep periodontal pockets and furcation areas via serum, and also affect organisms residing within gingival epithelium and connective tissue. Before advising any anti-microbial agent, it is necessary to have knowledge of that agent. The aim of this review article is to provide basic details of each systemic anti-microbial agent used in periodontal therapy. The points discussed are its mode of action, susceptible periodontal pathogens, dosage, its use in treatment of periodontal disease, and mechanism of bacterial resistance to each anti-microbial agent. It might be of some help while prescribing these drugs.
